Integrative genomics to identify emphysema-associated regulatory network

The goal of this project is to identify genomic regions associated with emphysema susceptibility and to functionally characterize a subset of these regions.  The approach is to combine GWAS and eQTL data to identify a likely set of disease-associated functional variants.  Then, by integrating these data with ENCODE and Roadmap project transcriptional regulatory data, detailed functional hypotheses for emphysema-associated loci are generated and subsequently explored via cell-based assays.

Dr. Peter Castaldi

Assistant Professor of Medicine

Dr. Peter J Castaldi, MD has a medical practice in Boston, Massachusetts. He specializes in internal medicine, and has over 13 years of experience in

Read more about Peter Castaldi
Channing Laboratory
181 Longwood Ave
Boston MA 02115
Castaldi PJ, Cho MH, Zhou X, Qiu W, McGeachie M, Celli B, Bakke P, Gulsvik A, Lomas DA, Crapo JD, et al. Genetic control of gene expression at novel and established chronic obstructive pulmonary disease loci. Hum Mol Genet. 2015;24 (4) :1200-10.Abstract

Genetic risk loci have been identified for a wide range of diseases through genome-wide association studies (GWAS), but the relevant functional mechanisms have been identified for only a small proportion of these GWAS-identified loci. By integrating results from the largest current GWAS of chronic obstructive disease (COPD) with expression quantitative trait locus (eQTL) analysis in whole blood and sputum from 121 subjects with COPD from the ECLIPSE Study, this analysis identifies loci that are simultaneously associated with COPD and the expression of nearby genes (COPD eQTLs). After integrative analysis, 19 COPD eQTLs were identified, including all four previously identified genome-wide significant loci near HHIP, FAM13A, and the 15q25 and 19q13 loci. For each COPD eQTL, fine mapping and colocalization analysis to identify causal shared eQTL and GWAS variants identified a subset of sites with moderate-to-strong evidence of harboring at least one shared variant responsible for both the eQTL and GWAS signals. Transcription factor binding site (TFBS) analysis confirms that multiple COPD eQTL lead SNPs disrupt TFBS, and enhancer enrichment analysis for loci with the strongest colocalization signals showed enrichment for blood-related cell types (CD3 and CD4+ T cells, lymphoblastoid cell lines). In summary, integrative eQTL and GWAS analysis confirms that genetic control of gene expression plays a key role in the genetic architecture of COPD and identifies specific blood-related cell types as likely participants in the functional pathway from GWAS-associated variant to disease phenotype.